Diferencias Niños Con Syndrome de Down

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OPEN Differences between children

with Down syndrome and typically
developing children in adaptive
behaviour, executive functions
and visual acuity
Christine de Weger1,2*, F. Nienke Boonstra1,3 & Jeroen Goossens1
In children with Down syndrome (DS) development of visual, motor and cognitive functions is
atypical. It is unknown whether the visual impairments in children with DS aggravate their lag
in cognitive development. Visual impairment and developmental lags in adaptive behaviour and
executive functions were assessed in 104 children with DS, 2–16 years, by comparing their adaptive
behaviour, executive functions and visual acuity (distant and near) scores against published age-
matched norm scores of typically developing children. Associations between these lags were explored.
Mean (± SEM) differences to age-matched norms indicated reduced performance in DS: Vineland
Screener questionnaire, − 63 ± 3.8 months; task-based Minnesota Executive Function Scale (MEFS),
− 46.09 ± 2.07 points; BRIEF-P questionnaire, 25.29 ± 4.66 points; BRIEF parents’ and teachers’
questionnaire, 17.89 ± 3.92 points and 40.10 ± 3.81 points; distant and near visual acuity, 0.51 ± 0.03
LogMAR and 0.63 ± 0.03 LogMAR (near − 0.11 ± 0.04 LogMAR poorer than distant). Adaptive behaviour
(Vineland-S) correlated with the severity of visual impairment (r = − 0.396). Children with DS are
severely impaired in adaptive behaviour, executive functions and visual acuities (near visual acuity
more severely impaired than distant visual acuity). Larger impairment in adaptive behaviour is found
in children with larger visual impairment. This supports the idea that visual acuity plays a role in
adaptive development.
Approximately 14.6 in 10,000 children are born with Down syndrome (DS), the most common genetic a nomaly1,2.
They have neurological deficits as well as visual impairments. Both of these may challenge the development of
functions that rely on executive control. However, it is unknown whether a relation exists between the visual
impairments in children with DS and their lag in cognitive development. Possibly, visual impairments aggravate
cognitive development. To study this relation, developmental lags in children with DS need to be specified and
quantified. Once we know what may be expected with regard to the development of a child with DS, research
on evidence-based interventions for this group could be initiated.
In children with DS, motor, cognitive, practical and social skills develop slower and to a lower level compared
with typically developing children3. Shortly after birth, there is growth and maturation, but it is slow. In the next
several months, the development of neuronal morphology of the visual cortex (where visual information is pro-
cessed), cerebellar and brain stem size, brain weight, skull size, and visual acuity slows down further4. Ocular
disorders also limit their visual acuity and visual functioning. These disorders include: frequently occurring and
severe refractive errors, nystagmus and accommodation lags (inability to accurately change the shape of the eye
lens to focus the image of near objects on the retina)5,6.
In children with isolated visual impairment, visual acuity limits the acquisition of skills needed to respond
appropriately to environmental demands across a range of contexts, so-called adaptive behaviour and execu-
tive functions7–12. Severe early-onset visual impairment is considered a major neurodevelopmental disorder.
It impacts multiple developmental processes, such as vulnerabilities in motor, cognitive, language, social and
1
Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Radboud University
Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. 2Bartiméus, Institute for the
Visually Impaired, Van Renesselaan 309, 3703 AJ Zeist, The Netherlands. 3Royal Dutch Visio, National Foundation
for the Visually Impaired and Blind, Huizen, The Netherlands. *email: c.deweger@donders.ru.nl
Scientific Reports | (2021) 11:7602 | https://doi.org/10.1038/s41598-021-85037-4 1
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Normative studies Source n = Age range (years)

Vineland-S Sparrow et al., 199315,16 979 0–6
MEFS Carlson, 201937 32,800 2–17
BRIEF-P Gioia et al., 200317,18 1747 2–5
BRIEF parents’ version Huizinga et al., 200920,21 3333 5–17
BRIEF teachers’ version Huizinga et al., 200920,21 941 5–11
Salomao et al., 199538 646 0–2.5
Pan et al., 201039 1722 2.5–6
Lai et al., 201140 212 3–6
Visual acuity (total n = 2985)
Huurneman et al., 201236 75 4–8
Jeon et al., 201041 78 5–11
Dobson et al., 200942 252 5–12
Table 1. Normative studies used. Published studies on typically developing children from which we extracted
normative data. For each test, the table lists the source of the normative data (i.e., the published study), the
number of included children and their age range.
attentional domains—all aspects of adaptive behaviour12. Studies by Sonckson and Dale7, Dale and Sonckson8
and Tadic et al.13 showed cumulative debilitating consequences on cognitive, language and social skills. Even
children with mild to moderate visual impairment show reduced adaptive behaviour. They have more difficulties
with skills that affect development and learning than well sighted, typically developing children11.
Executive functions are neurocognitive skills that serve as the foundation for early learning. These func-
tions include working memory, control over impulsive thoughts and behaviours, ability to think flexibly and
break habits that can get in the way of learning14. Differences in parent-rated executive functions were found
between school-aged children with all degrees of visual impairment and age-matched typically sighted, typically
developing children10. Children with severe to profound visual impairment had the greatest difficulties. With
teacher-ratings, Heyl and H intermair9 found that visually impaired students also performed poorer at school
than typically developing children. Compared to children in mainstream schools, visual impaired children at
special schools had even more problems in all domains of executive functions. Almost all domains of behav-
ioural problems and the executive function domains correlated. Although their study may have included some
children with DS at special schools, the relation between visual acuity and adaptive behaviour or development
of executive functions has not yet been studied in a large cohort of children with DS.
In addition to the learning difficulties associated with the typical malformation of central brain structures in
DS, visual impairment could also have an impact on the acquisition of skills needed to respond appropriately
to environmental demands. Children with DS attend regular schools where they have to find their way between
typically developing children, or they attend special schools where children with other demands surround them.
Insight in the development of adaptive behaviour and executive functions of children with DS in combination
with their limited visual acuity may contribute to better tailored therapeutic care and guidance at school.
The current study, therefore, compares adaptive behaviour, executive functions and visual acuity in children
with DS with published norm scores of typically developing children and analyses possible associations between
these different abilities. Adaptive behaviour and executive functions in everyday life were assessed using parents’
questionnaires, Vineland-Screener (Vineland-S)15,16, BRIEF-P17–19 and B RIEF20–22 questionnaires commonly used
in DS in clinical practice. The assessment of executive functions was complemented with the teachers’ question-
naire of BRIEF and a task-based test, the Minnesota Executive Function Scale (MEFS)23,24. Visual acuities were
assessed with symbol discrimination on visual acuity charts, LEA s ymbols25 or Kay pictures26.
Methods
The assessments presented here were part of a Randomized Controlled Trial (RCT) on the effects of wearing
bifocal eye glasses in children with DS27. The project was conducted in accordance with the tenets of the Decla-
ration of Helsinki. It was reviewed and approved by the Dutch Medical Ethics Committee of the Isala Hospitals
(NL48288.75.14/METC: 14.0333) and registered in ClinicalTrials.gov (NTC02241356). For the current cross-
sectional study, we used the baseline measurements of this RCT, i.e., before children were randomised in one of
the two treatment groups (bifocal or unifocal glasses). The data were collected at 15 participating locations in
the Netherlands, 14 hospitals and 1 institution for the visually impaired. Locations were geographically spread
across the country, serving both rural and urban populations of diverse social economic status.
Normative data were obtained from studies on typically developing children (see Table 1).
Participants. Written informed consent was obtained from both parents of each child, or from one parent
in case of single parenthood. Inclusion criteria included (1) diagnosis of Down syndrome, (2) age range from 2
to 18 years, (3) ability to respond (verbally or non-verbally) to vision tests if they were older than 5 years. Age
two, the age at which most children could sit and look downwards to their toys in their hands, was chosen as
youngest age for inclusion. A total of 104 children with DS between 2 and 16 years (23 and 205 months) old were
included. The children were recruited from participating locations in cooperation with the Dutch DS foundation
and many organizations of medical and allied health professionals who are involved in the medical guidance of
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Cohort characteristics n = % Mean Standard deviation

Number of children with DS 104
Boys 51 49
Children attending school 91 88
Children not using glasses 28 27
Nystagmus 17 16
Manifest strabismus 31 30
Age (months) 105.3 42.7
Accommodation lag (dioptres) 2.21 0.89
Manifest angle of strabismus (prism dioptres) 21.03 12.5
Distant visual acuity (LogMar) 0.43 0.26
Uncrowded near visual acuity (LogMar) 0.56 0.32
Crowded near visual acuity (LogMar) 0.64 0.29
Table 2. Cohort characteristics. Data are given either as numbers (n =) and percentages (%) or as mean with
standard deviation.
children with DS. Participants’ characteristics are listed in Table 2. More details about participants and study
design of the RCT are given in our previous papers27,28.
Assessment procedures. Procedures for assessments of visual functions and executive functions were
protocoled. The local investigators, orthoptists from the participating locations, were trained to perform unfa-
miliar orthoptic tests, to administer the MEFS as prescribed by Reflection Sciences, LLC, and to use the digital
research data manager ResearchManager29.
First, informed consent and the medical history was obtained from the parent(s). Next, a baseline orthoptic
assessment was performed, followed by an assessment of executive functions with the MEFS. Children wore
their habitual glasses during these assessments. If the child had no glasses prescribed, assessments were per-
formed without glasses. At the end of the first visit, the BRIEF-P or BRIEF (parents’ and teachers’ versions) and
Vineland-S questionnaires were handed out.
If a child became uncooperative, testing was stopped according to the Dutch code of conduct relating to
expressions of objection by people who are incapable of giving consent, minors or mentally disabled participating
in medical research (Code of conduct in the Netherlands 2002, NVK Code of conduct in the Netherlands 2001).
Reasons for missing data, as a result of a lack of cooperation or otherwise, were noted.
Adaptive behaviour, Vineland‑S questionnaire. Parents were asked to fill out the questionnaire Vineland-
Screener (Vineland-S15,16, either on paper or online. This questionnaire with 72 items covering the four domains
of adaptive behaviour—communication, socialization, daily living skills, and motor skills—was used to estimate
the adaptive behavioural age of the child. In typically developing children, the adaptive behavioural age (assessed
by their adaptive behaviour in the Vineland-S) equals their calendar age. In our study, we refer to this adaptive
behavioural age estimated with Vineland-S questionnaire as ‘Vineland adaptive behavioural age’. Control data
were obtained from Sparrow et al.15 (n = 979, age range 0–6 years).
Executive functions. Executive functions were measured in a task-based test (Minnesota Executive Function
Scale, MEFS) and complementary information30 was obtained with ratings of contextual executive function
performance by the children’s parents and teachers (BRIEF-P and BRIEF questionnaires).
Task‑based test of executive functions, MEFS. The MEFS is a standardized game-like test to measure executive
function and learning readiness in children24. It captures the gradual development of executive functions across
the entire preschool and subsequent elementary school period. The MEFS measures a combination of atten-
tion span, the ability to retain information, behavioural management and flexible thinking. It has been tested
in more than 32,800 typically developing children, aged 24–215 months, in the United States and is valid and
reliable (Intraclass Correlation: 0.94) across a wide range of executive f unctions23,24,31). The MEFS is an engaging
computer card-sorting game that is administered one-on-one with a child. In this rule-switch task, examiners
asked the participants to match a card to a target14,32,33. First, in teaching trials, the examiner directed the child to
match the cards on one dimension (colour; e.g., “green ones go here”, or shape: e.g., “lions go here”). After this,
the MEFS test includes 7 levels of increasing difficulty, determined by the rules and the images to sort. The 7 lev-
els (corresponding to test scores 10, 20, 30, 40, 50, 60, ≥ 70) are subdivided in decimals to indicate scores of sub-
sets. This test did not presume the verbal ability of the child and the cards are large enough to be distinguished
easily by subjects with reduced (near) vision with a visual acuity of 1.0 LogMAR. The test was administered on
an iPad Air (iPad Air 2, 16 GB—Screen with and height, 197 × 147 mm; resolution 1536 × 2560 pixels; pixel pitch
0.077 mm2). Children with DS tend to love games on tablets, so we typically obtained good cooperation of the
children with the MEFS.
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Rating‑based assessment of executive functions, BRIEF and BRIEF‑P questionnaires. To obtain informant
report, we asked the parents to fill out one of two questionnaires. Depending on the calendar age of the child,
this was either the BRIEF-P (Behavioural Rating Inventory of Executive Function for preschool age, designed for
the age range 2–5 years)17–19 or the BRIEF (Behavioural Rating Inventory of Executive Function, designed for the
age range 5 to 17 years)20–22. We also asked the parents to have the teacher fill out the teachers’ questionnaire of
the BRIEF (age range 5 to 11 years). The BRIEF and BRIEF-P questionnaires are designed to provide an ecologi-
cally valid real-world assessment of executive functions.
In our study, we adjusted the age limits of the BRIEF-P and BRIEF questionnaires to better match the admin-
istered questionnaire to the adaptive developmental age of children with DS. The BRIEF-P was intended for
participants under the age of 8, whereas the BRIEF was intended for participants older than 8 (see Table 3a).
The age limit of 8 years was based on the study of van Gameren et al.34 and personal communication with M.
Huizinga, author of the Dutch BRIEF q uestionnaire21,22. Van Gameren et al.34 found a developmental age in
children with DS of half their calendar age but with a wide confidence interval.
The BRIEF-P questionnaires collected ratings on 5 executive functions-scales: inhibition, shift (being flex-
ible in switching allocation of attention), emotional control, working memory, and plan/organize. The BRIEF
questionnaires, parents’ and teachers’ versions, collected ratings on 8 executive functions-scales: inhibition,
shift (being flexible in the allocation of attention), emotional control, initiate, working memory, plan/organize,
organizing of materials, and monitor. For each of the 63 (BRIEF-P) or 86 (BRIEF) statements, parents indicated
whether the particular behaviour described in the item had Never, Sometimes, or Often been a problem for
their child within the last six months. Teachers did so for 75 (BRIEF) statements. For each of these question-
naire types, we only considered the raw aggregated score across domains, the raw Global Executive Composite
(rGEC). Higher scores represent greater levels of executive function impairment.
Visual functions. Visual acuities—both at distant and at near—were assessed with their habitual glasses or
without glasses if the child did not use glasses. We applied non-verbal or verbal methods (matching or naming
LEA symbols25 or Kay p ictures26 on visual acuity charts) according to the capacity of the child. Distant visual
acuity was typically tested at 5 m with LEA linearly arranged cards or Kay Pictures. Uncrowded and crowded
near visual acuity was assessed binocularly at 40 cm with LEA symbols with absolute s pacing35,36. Near vision
was measured without bifocals, as only baseline measurements were included in this study. In case 40 cm was
not feasible because the child insisted to keep the card at a closer distance (n = 13), the actual distance (range 10
to 40 cm) was noted and visual acuity scores were corrected accordingly (although a shorter distance gives less
accurate near VA estimates)36.
Data analysis. Statistical analysis was performed using the statistical package for the social sciences (SPSS
version 23, IBM Inc., Chicago, IL).
Only questionnaires in which the number of filled in items passed the limits listed in the respective
manuals16,18,21 were included. We analysed the BRIEF-P, BRIEF parents’ version, and BRIEF teachers’ versions
separate from each other.
Because of the expected discrepancy between calendar age and the adaptive behavioural age for children with
DS, the BRIEF-P and BRIEF questionnaire data were not transformed into age-adjusted scores. Instead, we used
the raw scores (raw Global executive composite score, rGEC) for all our analyses. In this way, relations between
age and total difficulties could be evaluated. Subdomains of the Vineland-S or BRIEF-P and BRIEF questionnaires
were not analysed separately because the study focus was on a general developmental assessment. We also used
the raw MEFS score, the Total Score, as opposed to its norm-referenced score.
Continuous data are summarized by mean, standard deviation (SD) and range—nominal data by frequen-
cies and proportions. Student’s t-test and Chi-square test were applied to analyse group differences, respectively.
The scores of the Vineland-S, MEFS as well as the BRIEF-P, BRIEF and visual acuity data were all analysed as
a function of calendar age. Pearson correlations or Spearman correlations were computed, and data were com-
pared to norm scores (see Table 1). We used normative data of the Vineland-S15,16, n = 979, age range 0–6 years,
MEFS37, n = 32,800, age range 24 months–18 years, BRIEF-P17,18, n = 1747, age range 2–5 years, BRIEF parents’
version20,21, n = 3333, age range 5 -17 years and BRIEF teachers’ version21, n = 941, age range 5–11 years. The
normative data on visual acuity include several studies, total n = 2985, age range 0–12 years: Salomao et al.38,
n = 646, 0–36 months; Pan et al.39, n = 1722, 30 months–6 years; Lai et al.40, n = 212, 3–6 years; Huurneman et al.35,
n = 75, 4–8 years; Jeon et al.41, n = 78, 5–11 years; Dobson et al.42, n = 252, 5–12 years. For display purposes, a
Loess line fitted to the scores of the children with DS was plotted in Figs. 1, 2, 3 and 4.
To compare the data of children with DS to norm scores, we first calculated the difference between the score
of the child with DS and the corresponding norm score for that child’s calendar age (i.e., the developmental
lag). Thereafter, we analysed the difference scores in a One-sample t-test, to test if the mean of the difference
scores differed from zero. In a similar way, we also compared the MEFS scores of the children with DS to norm
scores corresponding to their Vineland adaptive behavioural age. For this analysis, we first calculated the differ-
ence between the score of the child with DS and the norm score matching the child’s adaptive behavioural age.
Thereafter, we tested the difference scores in a One-sample t-test.
The relation between the developmental lag and calendar age was analysed by linear regression. In the text,
B is the estimate of the slope that represents the average change in the dependent variable for a unit change in
the independent variable (age).
Visual acuity is typically assessed with uncrowded linearly arranged vision charts at distance. In our cohort,
distant visual acuity was assessed with uncrowded linearly arranged optotypes as well. Near visual acuity was
assessed in two ways, with uncrowded vision charts and with crowded vision charts. In our analyses, we used the
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Figure 1. Vineland Adaptive behaviour. Adaptive developmental age as estimated by their adaptive behaviour
in the Vineland-S, as a function of calendar age in 83 children with DS. Note that all scores fell below the norm
(identity line; n = 979, age range 1–72 months; Sparrow et al.15,16). According to the measurement focus of the
Vineland-S, the norm scores of typically developing children equal their calendar age. Blue bullets: Measured
boys with DS (n = 40). Red bullets: Measured girls with DS (n = 43). Solid green line: Loess line fitted to the data
of the children with DS pooled across boys and girls. Dotted purple line: (Expected) norm scores (mean) of
typically developing children pooled across boys and girls. Grey dashed lines: upper and lower bound of the 95%
confidence interval of norm scores of typically developing children.
uncrowded distant and near visual acuity assessments (assessed with uncrowded linearly arranged distant and
near vision charts). Because uncrowded distant visual acuity equals uncrowded near visual acuity in typically
developing children36, we used norm scores for distant visual acuity in analyses of near visual acuity as well.
To study the association of developmental lags (difference in scores between children with DS and age-
matched norm scores) in adaptive behaviour and executive functions with visual impairments, we used the
difference in distant visual acuity (expressed in LogMAR) between children with DS and age-matched norm
scores. In multivariate linear regressions of the lags in scores of Vineland adaptive behaviour and the different
executive functions assessments, the association with visual impairment was analysed in covariance with age,
gender and school attendance. These covariates were chosen according to findings of Papadopoulos et al.42 and
Metsiou et al.43. Information about school attendance was obtained from the parents and was irrespective of
duration or type of school. Thereafter, the influence of nystagmus and strabismus was analysed by entering these
measures as covariates in the multivariate linear regression.
Results
Figures 1, 2, and 3 show results from the Vineland-S, the MEFS, the BRIEF-P, and the BRIEF parents’ and teach-
ers’ versions. For completeness, each figure plots the data of boys and girls separately (boys in blue, girls in red),
but in our univariate analyses we have pooled the data across gender because there were no significant differences
between boys and girls in our cohort.
Vineland screener questionnaire. The Vineland Screener questionnaires were returned sufficiently filled
out by 83 (80%) of the parents.
The Vineland adaptive behaviour (expressed in an age in months) of our participants increased systematically
with their calendar age, resulting in a strong positive correlation between the two variables (r = 0.722, p < 0.001;
Spearman rank correlation, r = 0.718, p < 0.001) (see Fig. 1). Note, however, that this measure of adaptive behaviour
in children with DS fell below the norm score of typically developing children (identity line, derived from n = 979
children)15,16. The average difference between Vineland adaptive behaviour and calendar age in children with DS
was − 63 ± 35 months (t-test, t(82) = − 16.519, p < 0.001). The magnitude of this developmental lag also correlated
with calendar age. With increasing calendar age, the Vineland adaptive behaviour in DS was rated further behind
normal (r = 0.965, p < 0.001, B = − 0.78 ± SEM 0.02, R2 = 0.931). As inferred from the slope, B, of the regression line,
the development is about 80% slower in children with DS compared to the typically developing peers.
To detect possible bias, we compared the mean calendar age in the group of children with a filled in Vineland
questionnaire and those without (n = 83 and n = 21, respectively, p = 0.579). We found no differences.
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Figure 2. Task-based executive functions. Minnesota Executive Function Scale (MEFS) data of 86 children with
DS as a function of calendar age together with normative data (n = 32,800, age range 24–216 months; C arlson37).
Note lower MEFS scores in children with DS compared to the norm scores. Blue bullets: Measured boys with DS
(n = 43). Red bullets: Measured girls with DS (n = 43). Green curve: Loess line fitted to the data of the children
with DS pooled across boys and girls. Purple curve: Norm scores (mean) of typically developing children pooled
across boys and girls. Grey dashed lines: upper and lower bound of the 95% confidence interval of norm scores
of typically developing children.
Minnesota executive function scale. The MEFS was successfully administered in 86 (83%) participants
in the age range from 28 to 205 months. In Fig. 2, we first analysed the MEFS data as a function of calendar
age and compared the scores of our participants (n = 86) to the normative data of typically developing children
(n = 32,80037).
The mean MEFS score in the children with DS was 26.2 ± 14.9 points, range 0 to 55, whereas the mean of the
corresponding normative scores was 72.3 ± 22.4 points, range 15 to 92. The mean difference between the MEFS
scores of children with DS and the norm scores for children of the same calendar age was significant, − 46.1 ± 19.2
points, (t-test , t(85) = − 22.246, p < 0.001).
In line with the norm scores, the MEFS scores of participants with DS increased in association with their
calendar age (r = 0.484, p < 0.001). The magnitude of the lag in MEFS scores compared to norm scores also cor-
related with calendar age. With increasing calendar age, the MEFS scores of children with DS lie further below the
norm scores (r = 0.684, p < 0.001, B = − 0.32 ± SEM 0.04, R2 = 0.47). As inferred from the slope, B, of the regression
line, the development of executive functions as assessed with the MEFS is about 30% slower in children with DS.
We also analysed the relation between the MEFS data and adaptive behaviour (expressed as a calendar age
in months, estimated by the Vineland-S questionnaire). Towards that end, we compared the MEFS scores of
participants with DS (n = 86) to normative data of children of the same adaptive behavioural age. On average, the
MEFS scores of the children with DS coincide with the MEFS scores one could expect based on their Vineland
adaptive behaviour (mean difference 0.6 ± 13.9 points, t-test, t(64) = − 0.339, p = 0.736). Yet, it appeared that the
correlation of MEFS scores of DS participants with their Vineland adaptive behaviour (r = 0.545, p < 0.001) was
not significantly stronger than the correlation of MEFS scores in DS with their calendar age (r = 0.484, p < 0.001;
z = 2.51, p = 0.610).
Children who successfully performed the MEFS test were on average older than those who did not (mean age
109.2 ± 41.5 and 86.6 ± 44.5, t(102) = − 2.075, p = 0.040), and tended to have higher Vineland adaptive behaviour
(mean 42.0 ± 12.22 and 35.1, t(81) = − 1.702, p = 0.093).
BRIEF‑P and BRIEF questionnaires. For a total of 89 (86%) children, parents returned the executive
functions questionnaires. Some parents completed a questionnaire that did not meet the age range that we had
specified, or filled in both BRIEF-P and BRIEF questionnaires. For the analyses below, we used all questionnaire
results, provided the number of answered questions exceeded the minima specified in the BRIEF-P and BRIEF
protocol (see Table 3b and c).
In Fig. 3, the raw GEC scores of the questionnaires BRIEF-P, BRIEF parents’ and teachers’ versions are plotted
as a function of calendar age together with raw GEC norm scores. We found that the scores of children with DS
were on average above the norm (poorer executive functions) in all three questionnaires (mean age-matched
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Questionnaires executive functions

(a) Age ranges of questionnaires executive functions
Originally designed for age
range Adjusted age range to Down syndrome in our study
BRIEF-P 2–5 years 2–< 8 years
BRIEF parents’ version 5–18 years 8–18 years
BRIEF teachers’ version 5–12 years 8–18 years
(b) Number of questionnaires executive functions
Missing questionnaires meeting
Meeting the age range of the study Not meeting the age range of the the age range of the study
Questionnaires filled in protocol study protocol protocol
n = n = n = n =
BRIEF-P 49 30 (< 8 years) 19 (> 8 years) 11
BRIEF parents’ version 50 44 (> 8 years) 6 (< 8 years) 19
BRIEF teachers’ version 39 36 (> 8 years) 3 (< 8 years) 27
(c) Number of parents returning combinations of questionnaires
Combination with BRIEF Combination with both BRIEF-P
Only one questionnaire Combination with BRIEF-P parents’ and BRIEF parents’
n = n = n = n =
BRIEF-P 35
BRIEF parents’ version 11 3
BRIEF teachers’ version 3 25 11
Table 3. Questionnaire return. Age ranges and numbers of filled BRIEF-P and BRIEF questionnaires. (a)
The age ranges for which the questionnaires were originally designed as well as the adjusted age ranges
used of children with DS in the current study. (b) The number of filled in questionnaires. (c) The number of
combinations of questionnaires BRIEF-P, BRIEF parents’version and BRIEF teachers’version) which were
returned by the parents. n = number of participants.
differences: BRIEF-P, 25.3 ± 17.5 points, t-test, t(13) = 5.423, p < 0.001; BRIEF parents’ version, 17.9 ± 26.8 points,
t-test, t(45) = 4.568, p < 0.001; BRIEF teachers’ version, 40.1 ± 20.5 points, t-test, t(28) = 10.535, p < 0.001). None
of the scores of our participants correlated with calendar age (all p > 0.197), as was the case with the norm scores.
Only the teachers’ ratings on the BRIEF negatively correlated with Vineland adaptive behaviour (r = − 0.368,
p = 0.025) indicating that a higher level of adaptive behaviour was associated with better executive functions at
school.
In none of the BRIEF-P or BRIEF questionnaires, we found a difference in mean age or mean Vineland adap-
tive behaviour between the children whose questionnaire was filled in and whose questionnaire was missing.
Visual acuity. We found poor distant visual acuity in the children in DS as well as a poor near visual acuity.
Mean distant visual acuity was 0.43 ± 0.26 LogMAR (~ 0.37 decimal). Mean near visual acuity was 0.56 ± 0.32
LogMAR (~ 0.28 decimal). Their near visual acuity was on average poorer than their distant visual acuity (mean
difference 0.11 ± 0.32 LogMAR, paired t-test, t(73) = 2.900, p = 0.005). This is in contrast to typically developing
children in whom no consistent differences between near and distant visual acuities are f ound36. The difference
between near and distant visual acuity in children with DS did not correlate with their calendar age (r = − 0.76,
p = 0.520). Visual acuity measurements of our cohort are presented in comparison to the development of (dis-
tant) visual acuity during childhood in typically developing children (total n = 2985, age range 0–12 years,
including Salomao et al.38, n = 646, age range 0–30 months; Pan et al.39, n = 1722, age range 30–72 months; Lai
et al.40, n = 212, age range 3–6 years; Huurneman et al.35, n = 75, age range 4–8 years; Jeon et al.41, n = 78, age range
5–11 years; Dobson et al.42, n = 252, age range 5–12 years) in Fig. 4.
The average difference between distant visual acuity in children with DS and distant visual acuity of age-
matched typically developing children was 0.51 ± 0.25 LogMAR (~ 0.6 decimal) (t-test, t(90) = 19.597, p < 0.001)
whereas this difference was 0.63 ± 0.30 LogMAR (~ 0.7 decimal) for near visual acuity (t-test, t(75) = 18.175,
p < 0.001). These differences did not correlate with calendar age (both p > 0.5).
Associations between visual and cognitive impairments. We analysed the association of visual
impairment (i.e., the difference between visual acuity of children with DS and the age-matched visual acuity
norm scores), in particular distant visual impairment, with the lags in cognitive developmental scores of the
children with DS (i.e., the difference in scores between children with DS and norm scores of Vineland adaptive
behaviour, MEFS scores and BRIEF-P and BRIEF ratings). Following Papadopoulos et al.44 and Metsiou et al.43,
we adjusted for possible confounding factors, age, gender and school attendance. We ran separate multivari-
ate linear regressions on the lags in Vineland adaptive behaviour, MEFS scores and executive function ratings.
Reported q-values are p-values adjusted for multiple testing with false discovery rate (FDR) correction.
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Figure 3. Informant rated executive functions. (a) BRIEF-P results for children with DS younger than 8 years
(n = 49) Normative data (n = 1747, age 2–5 years) from Gioia et al.17,18. b) Parent’s version of the BRIEF for
children of 8 years and older with DS (n = 89). Normative data (n = 3333, age 5–17 years) from Huizinga
et al.20,21. c) Teacher’s version of the BRIEF for children of 8 years and older with DS (n = 39). Normative data
(n = 941, age 5–11 years) from Huizinga et al.20,21. Data of children with DS are typically above the norm
indicating that children with DS scored poorer on this executive functions scale. Blue bullets: Measured boys
with DS (BRIEF-P n = 27, BRIEF parents’ version n = 22, teachers’ version n = 18). Red bullets: Measured girls
with DS (BRIEF-P n = 22, BRIEF parents’ version n = 28, teachers’ version n = 21). Green curve: Loess line fitted
to the data from ratings on children with DS pooled across boys and girls. Blue curve: Norm scores (mean) of
typically developing boys. Red curve: Norm scores (mean) of typically developing girls. Light blue dashed lines:
upper and lower bound of the 95% confidence interval of norm scores of typically developing boys. Pink dashed
lines: upper and lower bound of the 95% confidence interval of norm scores of typically developing girls.
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Figure 3. (continued)
Figure 4. Visual acuity. Normative data from typically developing children (age 0–12 years) are shown in
red70 with upper and lower bound of the 95% confidence interval in grey dashed lines (extracted from the
separate original s tudies70). Note that before the age of 30 months, visual acuity could be estimated only with a
preferential looking test such as the Teller acuity chart (TAC)71. From the age of 30 months, visual acuity could
be assessed with symbols the child named, gestured or matched. Distant (green) and near (blue) visual acuity in
our cohort of children with DS as a function of calendar age. Solid lines are Loess lines fitted to the data. Note
the gradually improving visual acuity of children with DS and typically developing children. The acuities of the
children with DS lie above the norm scores indicating that children with DS scored poorly on visual acuity, near
visual acuity being even worse than distant visual acuity (mean difference 0.11 ± 0.32, paired t-test t(73) = -2.900,
p = 0.005). Normative distant visual acuities were obtained from: Salomao et al.38, (TAC, n = 646, 0–30 months,
red crosses), Pan et al.39 (HVOT, n = 1722, 30–72 months, red circles), Lai et al.40 (Landolt-C, n = 212, 3–6 years,
red stars), Huurneman et al.35 (Tumbling E, n = 75, 4–8 years, red x-es), Jeon et al.41 (Tumbling E, n = 78,
5–11 years, red triangles), Dobson et al.42 (ETDRS, n = 252, 5–12 years, red squares). Grey dashed lines: upper
and lower bound of the 95% confidence interval of the original norm data.
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r q B SE B
Distant visual impairment − 0.396 0.001 − 17.37 4.96
Calendar age − 0.964 < 0.001 − 0.846 0.03
Gender 0.164 0.287 5.48
School attendance − 0.23 0.055 − 10.69 8.47
Model − 0.968 < 0.001
Table 4. Association between visual acuity and Vineland adaptive behaviour. Multivariate analysis of the
correlation between the lag in Vineland adaptive behaviour and distant visual acuity impairment adjusting for
calendar age, gender and school attendance. r = partial correlation coefficient. q = significance of t-test adjusted
for multiple testing with false discovery rate (FDR) correction. B (unstandardized coefficients) = slope. SE
B = standard error of the mean of B.
The lag in Vineland adaptive behaviour was related to visual impairment; milder visual impairment was
associated with a smaller lag in Vineland adaptive development (see Table 4).
We analysed the correlation between the developmental lag in Vineland adaptive behaviour and the magni-
tude of visual impairment, adjusting for their calendar age, gender and school attendance. These impairments
were correlated (r = 0.396, q = 0.001). 94% of the variation in the lag of Vineland adaptive behaviour of the child
with DS was explained by the model (R2 = 0.937, model r = 0.968, q < 0.001). Here, both the magnitude of visual
impairment and calendar age had a significant correlation with the lag in Vineland adaptive behaviour (r = − 0.40,
q = 0.001, B = − 17.37 ± 5.0 and r = − 0.96, q < 0.001, B = − 0.85 ± 0.029, respectively). Going to school tended to
correlate with the lag in Vineland adaptive behaviour (r = − 0.23, p = 0.055, B = − 10.69 ± 8.5). The multivariate
linear regression analysis showed that an impairment of one LogMAR line (0.1 LogMAR) in distant visual acuity
was associated with a lag of 2 months in Vineland adaptive behaviour. One-month-older calendar age in DS was
associated with 0.9 months of additive lag in Vineland adaptive behaviour.
The differences in scores of MEFS, BRIEF-P and BRIEF of the children with DS with respect to the norm
scores of typically developing children were not correlated to the magnitude of visual impairment (all p > 0.184).
We also checked for a possible correlation of these cognitive developmental lags with nystagmus and stra-
bismus (the presence of strabismus or size of the manifest angle), two common ocular disorders in DS that can
influence visual acuity. In our data, the presence of nystagmus correlated with a lag in distant visual acuity
(r = 0.361, p = 0.001). However, in none of these regression analyses on the cognitive developmental lags, we
found significant correlations with nystagmus or strabismus.
Discussion
The current multicentre study investigated adaptive behaviour, executive functions and visual acuity in children
with DS, aged 2–16 years, in comparison to the age-matched norm scores of typically developing children. We
used a parent-rated questionnaire for adaptive behaviour (Vineland-S) and a combination of parent-rated and
teacher-rated questionnaires (BRIEF-P and BRIEF) as well as a task-based test (MEFS) for assessing executive
functions. Visual acuity was assessed with symbol discrimination on visual acuity charts at distance and at near.
Compared to typically developing children, children with DS had a lower outcome on adaptive behaviour
(Vineland-S), poorer outcome on executive functions according to both task-based (MEFS) and rating-based
(BRIEF-P and BRIEF) assessment, and poorer visual acuity. Their near visual acuity was even worse than their
distant visual acuity. Moreover, the lag in Vineland adaptive behaviour of children with DS was related to the
severity of their visual impairment.
Adaptive behaviour. In line with previous studies34,45–50, the children with DS in our study had weaker
adaptive behaviour than typically developing children. As found by Papadopoulos et al.44 in children with iso-
lated visual impairments (i.e., without DS), older children with DS performed better in the current study too.
But, they also showed a larger difference with typically developing children in comparison to younger children
with DS. We found the lowest scores in adaptive behaviour in children with poorest visual acuities. This new
finding in children with DS is in line with the reports of children with isolated visual impairment (without DS)
by Sonckson and Dale7, Dale and Sonckson8, Tadic et al.13 and Bathelt et al.11.
Even when we analysed the influence of visual acuity in covariance with age, we found the lowest performance
in the children with DS with the poorest visual acuities. This agrees with findings of Bathelt et al.11. They found
poorer adaptive behaviour—in practical, social and conceptual composite scores—in children (without DS)
with ascending levels of isolated visual impairment including mild to moderate and severe to profound visual
impairments.
As in afore mentioned studies in children with isolated visual impairment7,8,11,13, we only used the assessments
of distant visual acuity. Separate analyses of the influence of near visual acuity were omitted because there were
too many missing data.
MEFS and BRIEF‑P and BRIEF executive functions. In our study, children with DS had poorer execu-
tive function-outcomes than typically developing children in both task-based scores and in informant report
ratings. This agrees with previous s tudies51–57. In executive functioning assessed with the MEFS, we found an
association with calendar age. Older children with DS obtained higher MEFS scores, but they showed larger dif-
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ferences with norm data than younger children with DS. The scores show a large difference with age-matched
norm scores, but this reduced MEFS performance is in line with the performance one can expect from their
adaptive behaviour (estimated with Vineland-S questionnaire and expressed in age, months). The lack of cor-
relation of BRIEF-P and BRIEF ratings with calendar age in our study agrees with findings of Lee et al.57 and the
lack of correlation with age in norm data with findings of Gioia et al.17 and (Huizinga et al.21,22).
The MEFS scores of the children with DS were not clearly associated with their visual acuity. Thus, the MEFS
is suitable for children with visual impairment even though some vision is required to do the test.
Relation between adaptive behaviour scores and executive functions scores. Children with
poorer adaptive behaviour showed a lower score on the MEFS, which is in line with a recently published study in
children with DS by Sabat et al.58. The assessments they used resemble the combination of a questionnaire and a
card sorting test, MEFS, we used: ABAS-II parents’ and teachers’ v ersion59, and three executive functions tasks
including the Wisconsin Card Sorting Test60, respectively. Other researchers56 also reported weaker performance
on task-based executive functions tests in children with DS compared to children with normal development.
In our study, we found an inverse correlation of Vineland adaptive behaviour with BRIEF-teachers’ version but
not with the parents’ versions of the BRIEF and BRIEF-P questionnaires. Explanations for these discrepancies
between ratings of executive functions by teachers and by parents include the possibility that teachers and par-
ents are observing different behaviours or phenotypes. The more structured demands of school settings versus
relatively less organized home activities may challenge the children in a different w ay61,62. So, different inform-
ants may validly contribute unique information from different perspectives.
In the current study, the MEFS scores of children with DS were comparable to the norm scores of typically
developing children with the same level of adaptive behaviour. This relation shows the robustness of the Vineland-
S and MEFS and underlines the suitability of the MEFS for use in children with DS.
Visual acuity, distant and near. The differences in distant visual acuity and in near visual acuity between
children with DS and norm scores—poorer scores in children with DS—agree with previous p ublications5,63.
These differences did not change with age because of a similar improvement with age in children with DS and
in norm scores. Visual acuity develops slowly (see Fig. 4). Among other factors, the quality of the image on the
retina in childhood ages is very important64,65. The image quality on the retina can be optimized by correction of
refractive errors. In the current study, the children wore their habitual glasses or no corrections at all (i.e., usual
care). But, this may not have been the optimal situation because the refractive error can change more rapidly in
children with DS than in typically developing c hildren66. However, children with DS do not complain because of
low visual acuity. So, the need for adjustment of glasses may go unnoticed, unless regular screening is performed.
In the literature, this was analysed by van Splunder et al.67. Prior to their large study on visual impairment in
1598 adults with DS in the Netherlands, visual impairment or blindness had remained undiagnosed in 40.6% of
the persons. By contrast, typically developing children frequently do complain when their corrections are not
optimal anymore. We, therefore, can expect that the typically developing children, from whom the norm scores
were derived, getting usual care, had better corrections compared to the children with DS. Thus, non-optimal
correction of refractive errors by suboptimal glasses may have played a role in the large difference in visual acuity
between children with DS and typically developing children.
Apart from non-optimal corrections, other factors may have played a role. The abnormal morphology of the
visual cortex in children with D S4 induces impairment in cerebral visual processing, so called cerebral visual
68
impairment (CVI) . Thus, probably, the differences in visual acuity between children with DS and typically
developing children also are the result of CVI in children with DS. CVI includes accommodation lags and
crowding problems69. Accordingly, we found accommodation lags resulting in low near visual acuity and the
poor crowded near visual acuity in all of our participants (see Table 2).
The observed difference between distant and near visual acuity in children with DS is mainly due to accom-
modation lags with non-optimal refractive corrections. In our RCT, we found that the difference between distant
and near visual acuity in children with DS can be minimized with optical corrections tailored to the ocular dis-
orders of children with D S27. Wearing full correction of refractive error can maximize distant visual acuity and
partly support near visual acuity. Additionally, wearing bifocal glasses, the extra correction for looking at short
distances stimulates the development of near visual a cuity27 and thus reduces the difference between distant and
near visual acuity in children with DS.
Strengths and limitations. Strengths of the current study include: the large sample size with a relatively
rare and biologically well-defined condition (DS), the robust and standardised measurements that made data
collection across multiple sites possible, the use of both task-based and informant-based measures of executive
function, and the consideration of both adaptive developmental age (estimated from their adaptive behaviour in
the Vineland-S questionnaire) and calendar age. In addition, this is the first study in children with DS to assess
task-based executive functions with the MEFS.
Limitations of the study include the fact that normative data, being derived from other studies, may have
been collected under different experimental conditions. However, all these studies included large groups (see
Table 1). Norm scores of the Vineland-S and BRIEF-P had a limited age range (from 0 to 6 years and from 2
to 5 years, respectively), which limited comparisons with older children. Furthermore, as 90% of the included
children needed updated g lasses27, a variable part of the visual impairments may have been due to insufficient
correction of refractive errors. These avoidable impairments might have obscured a relation between executive
functioning and the level of best-corrected visual acuity.
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We also encountered difficulties in the acquisition of data, resulting in missing data. This was partly due to
practical issues (no iPad with the MEFS test available), but mostly due to a lack of cooperation of the participants
during the assessments on the one hand, and parental inattentiveness in returning completed questionnaires
on the other. It is known that in children with DS, as in other children with cognitive disabilities, cooperation
difficulties can emerge. In our cohort of children with DS, in which children were not selected because of high
level functioning or cooperation, these difficulties were unavoidable. The local examiners all had volunteered
to cooperate in this study and did their utmost to collect the data. Despite their motivation to obtain the neces-
sary measurements, they sometimes had to skip a test, or stop the measurements according to the Dutch code
of conduct relating to expressions of objection by people who are incapable of giving consent (2002). However,
of all the scores we collected, only the MEFS scores may have been affected by an age difference between the
group of children whose scores were available and whose data were missing. By including young children with
DS regardless of their developmental delay, it was unavoidable that we encountered children whose adaptive
behaviour was not proficient enough to perform the MEFS test (designed for children without cognitive delay
from the age of 2 years).
Finally, a cross-sectional analysis, as was performed in the current paper, has inherent limitations. It compares
participants to estimate the development of skills with increase of age. In this particular case, it is obvious that
the sample of children with DS is much more heterogeneous in terms of achieving adaptive skills or executive
functions than a non-clinical typical developing sample. This clearly underlines the need for a longitudinal design
in order to understand better the development of adaptive behaviour and executive functions in children with
DS and its relation with visual acuity.
Implications of the differences found between DS and typically developing children. Children
with DS attend regular schools or special schools, both with only a minority of children with DS. Being aware of
the specific limitations in abilities of this syndrome can be a support to parents, teachers and other profession-
als in the management and guidance of children with DS. Regular, targeted screening can detect, specify and
quantify the developmental lags and estimate the specific need of the individual child with DS. Interventions
or adaptations might be developed and applied to support and stimulate development to, at least partly, reduce
the developmental lags in children with DS. Optimizing visual functions with corrective glasses tailored to the
ocular disorders of children with DS is one of these interventions. Possibly, besides improving visual func-
tions, it may stimulate development on different levels, including adaptive behaviour and executive functions.
A cumulative impact of one of the delays in development on other developmental processes, already mentioned
and shown in children with isolated visual impairments7,8,13, might also exist in children with DS. In the current
study, a significant relation between visual acuity impairment and a lag in Vineland adaptive behavioural was
found. It has still to be proven that interventions are useful in decreasing differences, which otherwise, according
to our findings, get larger with increasing age. It is also not yet clear what the developmental range is in children
with DS with optimal corrections and interventions.
Conclusions. Children with DS in the age range of 2–16 years are severely impaired in adaptive behaviour,
executive functions and visual acuities (both distant and near). Larger impairments in Vineland adaptive behav-
iour are associated with larger impairments in visual acuity. This supports the idea that visual acuity plays a role
in the development of adaptive behaviour, as previously suggested for visually impaired children without known
developmental disorders. Furthermore, near visual acuity is more severely impaired in DS than distant visual
acuity, presumably because of the accommodation lag in DS. These findings emphasize the necessity of regular
screening during development in DS and, if possible, the application of interventions or adaptions.
Received: 31 October 2020; Accepted: 18 February 2021
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Acknowledgements
We thank all the participants of this study and their parents, the research assistants Y. Kras and L. van der Helm,
and all the orthoptists of the participating locations. Without their co-operation, we had not been able to perform
this study. Co-operation parties for this research were as follows: Isala Academy, SDS, TNO, DOC and all the
participating locations: Isala Klinieken Zwolle, Medisch Centrum Leeuwarden, Ziekenhuis de Tjongerschans
Heerenveen, Refaja Ziekenhuis Stadskanaal, Diaconessenhuis Meppel, Ziekenhuis St Jansdal Harderwijk, Dia-
konessenhuis Utrecht, Flevoziekenhuis Almere, Medisch Centrum Alkmaar, Vlietland Ziekenhuis Schiedam,
MCHaaglanden den Haag, Elisabeth Ziekenhuis Tilburg, Twee Steden Ziekenhuis Tilburg en Waalwijk, Wil-
helmina Ziekenhuis Assen and Royal Dutch Visio. This study was financially supported by ODAS, Oogfonds,
Novartis and LSBS (Uitzicht 2013-23 to F.N.B. and J.G., and Bartimeus Institute to F.N.B. and C.d.W.). These
financial parties had no influence on the design and the progress of the study.
Author contributions
C.d.W, wrote the manuscript text and prepared the figures & tables. F.N.B. reviewed the manuscript text, the
figures & tables. J.G. reviewed the manuscript text, the figures & tables.
Competing interests
The authors declare no competing interests.
Additional information
Correspondence and requests for materials should be addressed to C.W.
Reprints and permissions information is available at www.nature.com/reprints.
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Diferencias Niños Con Syndrome de Down

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OPEN Differences between children

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Normative studies Source n = Age range (years)

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Cohort characteristics n = % Mean Standard deviation

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Questionnaires executive functions

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Received: 31 October 2020; Accepted: 18 February 2021

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© The Author(s) 2021

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